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Trisubstituted thioxanthines

a technology of thioxanthines and substituted thioxanthines, which is applied in the field of trisubstituted thioxanthines, can solve the problems of narrow therapeutic index, increase in both force and rate of cardiac contractility, and limited number of structural classes of pde iv inhibitors, and achieve the effect of superior pde iv inhibitory

Inactive Publication Date: 2001-07-31
EURO-CELTIQUE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

It is a further object of the present invention to provide new compounds which have a superior PDE IV inhibitory effect as compared to theophylline, disubstituted 6-thioxanthines or other known compounds.

Problems solved by technology

However, theophylline is known to have a narrow therapeutic index, and a wide range of untoward side effects which are considered problematic.
While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited.
On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility.
These are undesirable side effects for an anti-inflammatory agent.
Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation.
However, although some have been suggested to be useful for treating, e.g., asthma, the specific anti-PDE IV activity of these compounds has not been determined.

Method used

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  • Trisubstituted thioxanthines
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  • Trisubstituted thioxanthines

Examples

Experimental program
Comparison scheme
Effect test

example 1

1,3-Diethyl-8-cyclopropyl-2,6-dithioxanthine

A. 1,3-Diethyl-8-cyclopropyl-2-thioxanthine

25.1 g (100 mM) of 5,6-diamino 1,3-diethyl-2-thiouracil HCl were dissolved in 400 ml of pyridine, 12.72 g (120 mM) of sodium carbonate added, and under cooling a solution of 10.77 ml (120 mM) of cyclopropane carbonyl chloride in 50 ml of dried ether added within 10 minutes. After 20 min the solvents were evaporated in vacuo. The residue was treated with 200 ml of water and about 50 ml were removed again in vacuo. The suspension was diluted with 100 ml of 2N aqueous sodium hydroxide (NaOH) and heated under reflux for 30 minutes. A further 80 ml was distilled off during this time. After cooling the solution was acidified with 5N aqueous hydrochloric acid (HCl) to pH 5.5; 200 ml of water was added and the resulting suspension filtered. The solid was collected and washed, redissolved in 200 ml of 1N NaOH, treated twice with 0.4 g of charcoal, filtered and acidified again to pH 4.5. The solid was colle...

example 2

3-(4-Chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine

A. 3-(4-Chlorobenzyl)-1-ethyl-8-isopropyl-xanthine

13.47 g (40 mM) of 6-amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracil were dissolved in 130 ml of DMF, treated at 5.degree. C. with 4.57 g (40.8 mM) potassium t-butoxide and after dissolution, 3.28 ml (44 mM) of ethyl bromide added. After 3 hours, another 1.14 g of t-BuOK and 1.64 ml of ethyl bromide were added. After a further 1.5 hours, 1.64 ml of ethyl bromide was supplemented. After a total of 22 hours, the solution was neutralized with 1N HCl to pH 7 and the solvents evaporated in vacuo. The residue was taken up in dichloromethane-water and the organic phase collected giving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of 1N NaOH and heated under reflux for 1 hour. The solution was treated twice with 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The solid was diluted with water, collected, and dried. The crude material was recrystallized from ...

example 3

1-(4-Chlorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine

A. 1-(4-Chlorobenzyl)-3-ethyl-8-isopropyl-xanthine

3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to a solution of 6.11 g (27.5 mM) of 6-amino-1-ethyl-5-isobutyrylamino-uracil. At 0.degree. C., 4.90 g (30.4 mM) of 4-chlorobenzylchloride were added. After 3 hours at 0-5.degree. C., further 1.22 g t-BuOK and 2.45 g of 4-chloro-benzylchloride were added. After further 3 hours another 2.45 g of benzylchloride are supplemented. After 3 days, the solution was neutralized with 1N HCl and the solvents evaporated. The residue was suspended in water, the solid collected and washed. The crude intermediate amide was heated under reflux in 100 ml of 1N NaOH and 10 ml of 1-propanol. After 1 hour, the mixture was neutralized to pH 7 and extracted with chloroform. Crystallization from dichloromethane (mainly evaporated)-methanol gave 2.99 g (31.3%) of the title xanthine, mp 194-5.degree. C. The mother liquors gave 6.33 g of impure ma...

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Abstract

Disclosed is a compound selected from the group consisting of 1,3,8-triethyl-2,6-dithioxanthine; 1,3,8-triethyl-2-thioxanthine; 8-cyclopropyl-1-ethyl-3-(2-methyl-butyl)-6-thioxanthine; 1,3-diethyl-8-isopropyl-6-thioxanthine; 8-cyclopropyl-1,3-dipropyl-6-thioxanthine; 8-isopropyl-1,3-dipropyl-6-thioxanthine; 1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine; 1-(4-chlorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine; and 8-cyclopropyl-1,3-diethyl-6-thioxanthine. Also disclosed is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound selected from the group above. Also disclosed is a method of effecting PDE IV inhibition which comprises administering to a patient suffering from a disease or disorder selected from the group consisting of asthma, allergies, PDE IV modulated inflammation, and depression, a therapeutically effective amount of a compound selected from the group above.

Description

Asthma is a complex disease involving the concerted actions of multiple inflammatory and immune cells, spasmogens, inflammatory mediators, cytokines and growth factors. In recent practice there have been four major classes of compounds used in the treatment of asthma, namely bronchodilators (e.g., beta-adrenoceptor agonists), anti-inflammatory agents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g., cromolyn sodium) and xanthines (e.g., theophylline) which appear to possess both bronchodilating and anti-inflammatory activity.Theophylline has been a preferred drug of first choice in the treatment of asthma. Although it has been touted for its direct bronchodilatory action, theophylline's therapeutic value is now believed to also stem from anti-inflammatory activity. Its mechanism of action remains unclear. However, it is believed that several of its cellular activities are important in its activity as an anti-asthmatic, including cyclic nucleotide phosphodiesterase in...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D473/38C07D473/20C07D473/00
CPCC07D473/38C07D473/20A61P11/06
Inventor CAVALLA, DAVIDHOFER, PETERCHASIN, MARK
Owner EURO-CELTIQUE SA
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